Notice

June 10, 2003

Our file number: 03-111093-252

Health Canada is pleased to announce the finalization of the Guidance
for Industry Stability Testing of Existing Drug Substances and Products.
This guidance is an extension of the previously released ICHFootnote 1 / Health Canada guidance document entitled Stability Testing of New
Drug Substances and Products (also referred to as the "parent
guidance") and defines the stability data package in submissions
for "existing" drug substances and associated products. In the
interests of international harmonization, wherever possible, this guidance
conforms to the principles of the ICH parent <guidance>, with changes
necessary to reflect the recommendations for existing drugs indicated
by "<text>".

A draft version of this document of the same title was released for Stakeholder
consultation in 1997. This finalized version has been to updated include
revisions as a result of the maintenance of the parent guidance, additional
clarification as a result of comments that have been received (where appropriate),
as well as to promote consistency with other Health Canada guidance documents.
A summary of the notable updates is provided in Attachment 1 to this Notice.

The effective date (with the exception of the Intermediate Storage Condition)
of this guidance document is April 1, 2004. The stability data package
for submissions received after this date should follow the recommendations
of this guidance. Mid-stream switch of the intermediate storage condition
from 30°C ± 2°C/60% RH ± 5% RH to 30°C ± 2°C/65%
RH ± 5% RH can be appropriate provided that the respective storage
conditions and the date of the switch are clearly documented and stated
in the registration application. It is recommended that submissions
contain data from complete studies at the intermediate storage condition
30°C ± 2°C/65% RH ± 5% RH, if applicable, by April 1, 2006.

This guidance document makes reference to another Health Canada guidance
document entitled Impurities in Existing Drug Substances and Products.
Health Canada is in the process of finalizing this document which will
replace the draft version released in 1999 entitled Identification,
Qualification, and Control of Related Impurities in Existing Drugs.

recommendations for drug substances and products intended for storage
at low temperature conditions and for drug products packaged in semi-permeable
containers;

guidance for the stability testing and specification of drug products
containing antimicrobial preservatives;

revisions to the storage conditions as per ICHQ1A(R2) have been incorporated
(as result of Q1F) (e.g., the Intermediate storage condition has been
changed from 30°C ± 2°C/60% ± 5% to 30°C ± 2°C/65%
± 5%);

guidance has been provided on examples of various scenarios for stability
designs (e.g., multiple strengths of identical or closely related formulations);

clarification on approaches for "release and shelf life specifications"
versus "regulatory acceptance criteria";

guidance on the establishment of storage statements for labelling
purposes.

(3) Consistencies with other Health Canada guidance documents:

the Scope of the guidance has been clarified to include Supplemental
New Drug Submissions (SNDSs), Supplemental Abbreviated New Drug Submissions
(SANDSs), and Notifiable Changes (NCs);

description on the definition of the start of a retest date;

the selection of batches has been revised to correspond with ICHQ1A
(e.g., including the definition for pilot scale), with changes
to accommodate existing drugs (e.g., One of the two batches should be
at least pilot scale batches and the second one can be smaller,
if justified (e.g., for solid oral dosage forms, 25 000 or 50 000 tablets
or capsules);

the evaluation of the stability data should follow the recommendations
of the ICHQ1E < guidance > (including the amount of extrapolation beyond
the available long term data);

guidance on the Continuing Stability Programme;

the minimum time period covered by data at the time of submission
at the accelerated storage condition was revised from 3 months to 6
months with a testing frequency having a minimum of three time points
(e.g., 0, 3, and 6 months) to be consistent with the Q1C guidance.

Foreword

Guidance documents are meant to provide assistance to industry and health
care professionals on how to comply with the policies and governing
statutes and regulations. They also serve to provide review and compliance
guidance to staff, thereby ensuring that mandates are implemented in a
fair, consistent and effective manner.

Guidance documents are administrative instruments not having force of
law and, as such, allow for flexibility in approach. Alternate approaches
to the principles and practices described in this document may
be acceptable provided they are supported by adequate scientific
justification. Alternate approaches should be discussed in advance with
the relevant program area to avoid the possible finding that applicable
statutory or regulatory requirements have not been met.

As a corollary to the above, it is equally important to note that Health
Canada reserves the right to request information or material, or define
conditions not specifically described in this guidance, in order to allow
the Department to adequately assess the safety, efficacy or quality of
a therapeutic product. Health Canada is committed to ensuring that such
requests are justifiable and that decisions are clearly documented.

This document should be read in conjunction with the accompanying notice
and the relevant sections of other applicable guidances.

1 Introduction

1.1 Objectives of the Guidance

<This guidance is an extension of the previously released ICHFootnote 3 /Health Canada guidance document entitled Stability Testing of New
Drug Substances and Products and defines the stability data package
in submissions for existing drug substances and associated products. An
"existing drug" is one that is not a new active substance but
requires the filing of a New Drug Submission (NDS), an Abbreviated New
Drug Submission (ANDS) or a Supplement for which a Notice of Compliance
has been previously issued pursuant to Division C.08 of the Food and
Drug Regulations (e.g., generic products). This could also include
submissions for new dosage forms, new strengths Footnote 4.
This guidance may also be used when determining stability requirements
for Notifiable Changes.>

1.2 Scope

<This guidance addresses the stability information to be included
on existing drug substances and associated drug products in new drug submissions
(NDSs) and abbreviated new drug submissions (ANDSs), Supplements and Notifiable
Changes.

For determination of stability requirements to Notifiable Changes, this
guidance may be used in conjunction with the Health Canada policy Stability
Requirements for Changes to Marketed New Drugs.

This guidance applies to pharmaceutical drugs, including synthetic drugs
and semi-synthetic drugs. This guidance does not apply to biologics or
radiopharmaceuticals.

The ICH harmonised tripartite guidance Stability Testing of New Drug
Substances and Products was originally adopted as a Health Canada
guidance in the fall of 1994. This guidance defines the stability data
package in submissions for new molecular entities and associated products.
The scope of the guidance further states that "This guideline does
not currently seek to cover the information to be submitted for abbreviated
or abridged applications, ...". The present guidance serves to delineate
the stability data package for existing drug substances and products.

In the interests of international harmonization, wherever possible,
this guidance conforms to the principles of the ICH Guidance Document
Q1A(R2) Stability Testing of New Drug Substances and Products,
with changes necessary to reflect the recommendations for existing drugs
indicated by "<text>".>

1.3 General Principles

The purpose of stability testing is to provide evidence on how the quality
of a drug substance or drug product varies with time under the influence
of a variety of environmental factors such as temperature, humidity, and
light, and to establish a retest period for the drug substance or a shelf
life for the drug product and recommended storage conditions.

<Alternate approaches to the principles and practices described in
this guidance may be acceptable provided they are supported by adequate
scientific justification. However, submission sponsors are encouraged
to discuss significant variations with Health Canada in advance to avoid
rejection or withdrawal of the submission.>

2 Guidance

2.1 Drug Substance

2.1.1 General

Information on the stability of the drug substance is an integral part
of the systematic approach to stability evaluation.

<The retest period is based on the results of long term stability
studies performed by the drug substance manufacturer or the submission
sponsor using validated analytical procedures.

The start of the retest period should begin at the date of manufacture
of the drug substance. The retest date of the blended batch should be
based on the manufacturing date of the oldest tailings or batch in the
blend.

In certain cases, information available in the public domain may be
sufficient to establish an appropriate retest period, e.g., if the synthetic
route and manufacturing process are identical and a substantial body of
evidence exists that establishes that the drug is inherently stable. In
all instances, sponsors are encouraged to provide all relevant information
available on the stability of the drug substance.

Submission sponsors should either:

assign a retest period for the drug substance based on the available
stability data, after which any batch should be retested for compliance
with specification and then used immediately (e.g., within 30 days of
testing),

or

certify that the drug substance will be tested for compliance
with specification immediately prior to use in the manufacture of the
drug product. In this case, formal stability studies on the drug substance
will not be necessary.

When available, relevant stability data available in the public domain,
including information in official pharmacopoeias, or from drug substance
(active pharmaceutical ingredient) manufacturers should be provided.>

2.1.2 Stress Testing

Stress testing of the drug substance can help identify the likely degradation
products, which can in turn help establish the degradation pathways and
the intrinsic stability of the molecule and validate the stability indicating
power of the analytical procedures used. The nature of the stress testing
will depend on the individual drug substance and the type of drug product
involved.

Stress testing is likely to be carried out on a single batch of the
drug substance. It should include the effect of temperatures (in 10°C
increments (e.g., 50°C, 60°C, etc.) above that for accelerated testing),
humidity (e.g., 75% RH or greater) where appropriate, oxidation, and photolysis
on the drug substance. The testing should also evaluate the susceptibility
of the drug substance to hydrolysis across a wide range of pH values when
in solution or suspension. Photostability testing should be an integral
part of stress testing. The standard conditions for photostability testing
are described in ICHQ1B.

Examining degradation products under stress conditions is useful in
establishing degradation pathways and developing and validating suitable
analytical procedures. However, it may not be necessary to examine specifically
for certain degradation products if it has been demonstrated that they
are not formed under accelerated or long term storage conditions.

Results from these studies will form an integral part of the <submission>.

2.1.3 Selection of Batches

Data from formal stability studies should be provided on at least <two>
primary batches of the drug substance. The batches should be manufactured
to a minimum of pilot scale by the same synthetic route as, and using
a method of manufacture and procedure that simulates the final process
to be used for, production batches. The overall quality of the batches
of drug substance placed on formal stability studies should be representative
of the quality of the material to be made on a production scale.

Other supporting data can be provided.

<When differences are identified in the production of the drug substance,
e.g., owing to the use of different drug substance manufacturers, stability
studies may not be necessary on material from each source provided that
the same synthetic route is used and batch analyses conducted by the
submission sponsor confirms that material from all sources or production
methods meet the sponsor's specifications, including purity, potency and
when relevant, crystal form and moisture. In such instances, the potential
impact on retest periods of differences in the container closure system
to be used by different drug substance manufacturers should be assessed.>

2.1.4 Container Closure System

The stability studies should be conducted on the drug substance packaged
in a container closure system that is the same as or simulates the packaging
proposed for storage and distribution.

2.1.5 Specification

Specification, which is a list of tests, reference to analytical procedures,
and proposed acceptance criteria, is addressed in ICHQ6A. In addition,
specification for degradation products in a drug substance is discussed
in Q3A <and Health Canada's Impurities in Existing Drug Substances
and Products.>

Stability studies should include testing of those attributes of the
drug substance that are susceptible to change during storage and are likely
to influence quality, safety, and/or efficacy. The testing should cover,
as appropriate, the physical, chemical, biological, and microbiological
attributes. Validated stability-indicating analytical procedures should
be applied. Whether and to what extent replication should be performed
will depend on the results from validation studies.

2.1.6 Testing Frequency

For long term studies, frequency of testing should be sufficient to
establish the stability profile of the drug substance. For drug substances
with a proposed retest period of at least 12 months, the frequency of
testing at the long term storage condition should normally be every 3
months over the first year, every 6 months over the second year, and annually
thereafter through the proposed retest period.

At the accelerated storage condition, a minimum of three time points,
including the initial and final time points (e.g., 0, 3, and 6 months),
from a 6-month study is recommended. Where an expectation (based on development
experience) exists that results from accelerated studies are likely to
approach significant change criteria, increased testing should be conducted
either by adding samples at the final time point or by including a fourth
time point in the study design.

When testing at the intermediate storage condition is called for as
a result of significant change at the accelerated storage condition, a
minimum of four time points, including the initial and final time points
(e.g., 0, 6, 9, 12 months), from a 12-month study is recommended.

2.1.7 Storage Conditions

In general, a drug substance should be evaluated under storage conditions
(with appropriate tolerances) that test its thermal stability and, if
applicable, its sensitivity to moisture. The storage conditions and the
lengths of studies chosen should be sufficient to cover storage, shipment,
and subsequent use.

The long term testing should cover a minimum of <6> months' duration
on at least <two> primary batches at the time of submission and
should be continued for a period of time sufficient to cover the proposed
retest period. Additional data accumulated during the assessment period
of the registration application should be submitted to the authorities
if requested. Data from the accelerated storage condition and, if appropriate,
from the intermediate storage condition can be used to evaluate the effect
of short term excursions outside the label storage conditions (such as
might occur during shipping).

Long term, accelerated, and, where appropriate, intermediate storage
conditions for drug substances are detailed in the sections below. The
general case applies if the drug substance is not specifically covered
by a subsequent section. Alternative storage conditions can be used if
justified.

2.1.7.1 General Case

Study

Storage condition

Minimum time period
covered by data at submission

It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

Long-term

25°C ± 2°C / 60% RH ± 5%
or 30°C ± 2°C/65% RH ± 5% RH

<6> months

Intermediate

30°C ± 2°C/65% RH ± 5% RH

6 months

Accelerated

40°C ± 2°C / 75% RH ± 5%

6 months

If long-term studies are conducted at 25°C ± 2°C/60% RH ±
5% RH and "significant change" occurs at any time during 6 months'
testing at the accelerated storage condition, additional testing at the
intermediate storage condition should be conducted and evaluated against
significant change criteria. Testing at the intermediate storage condition
should include all tests, unless otherwise justified. The initial application
should include a minimum of 6 months' data from a 12-month study at the
intermediate storage condition.

"Significant change" is defined as failure to meet the specification.

2.1.7.2 Drug Substances Intended for Storage in a Refrigerator

Study

Storage condition

Minimum time period covered by data at submission

Long term

5°C ± 3°C

<6> months

Accelerated

25°C ± 2°C/60% RH ± 5% RH

6 months

Data from refrigerated storage should be assessed according to the evaluation
section of this guidance, except where explicitly noted below.

If significant change occurs between 3 and 6 months' testing at the accelerated
storage condition, the proposed re-test period should be based on the
real time data available at the long term storage condition.

If significant change occurs within the first 3 months' testing at the
accelerated storage condition, a discussion should be provided to address
the effect of short term excursions outside the label storage condition,
e.g., during shipping or handling. This discussion can be supported, if
appropriate, by further testing on a single batch of the drug substance
for a period shorter than 3 months but with more frequent testing than
usual. It is considered unnecessary to continue to test a drug substance
through 6 months when a significant change has occurred within the first
3 months.

2.1.7.3 Drug Substances Intended for Storage in a Freezer

Study

Storage condition

Minimum time period covered by data at submission

Long term

- 20°C ± 5°C

<6> months

For drug substances intended for storage in a freezer, the re-test period
should be based on the real time data obtained at the long term storage
condition. In the absence of an accelerated storage condition for drug
substances intended to be stored in a freezer, testing on a single batch
at an elevated temperature (e.g., 5°C ± 3°C or 25°C ± 2°C)
for an appropriate time period should be conducted to address the effect
of short term excursions outside the proposed label storage condition,
e.g., during shipping or handling.

2.1.7.4 Drug Substances Intended for Storage below -20°c

Drug substances intended for storage below -20°C should be treated on
a case-by-case basis.

2.1.8 Stability Commitment

When available long term stability data on primary batches do not cover
the proposed re-test period granted at the time of approval, a commitment
should be made to continue the stability studies post approval in order
to firmly establish the re-test period.

Where the submission includes long term stability data on <two>
production batches covering the proposed retest period, a post approval
commitment is considered unnecessary. Otherwise, one of the following
commitments should be made:

If the submission includes data from stability studies on at least
<two> production batches, a commitment should be made to continue
these studies through the proposed retest period.

If the submission includes data from stability studies on fewer than
<two> production batches, a commitment should be made to continue
these studies through the proposed retest period and to place additional
production batches, to a total of at least < two>, on long term
stability studies through the proposed retest period.

If the submission does not include stability data on production batches,
a commitment should be made to place the first <two> production
batches on long term stability studies through the proposed retest period.

The stability protocol used for long term studies for the stability
commitment should be the same as that for the primary batches, unless
otherwise scientifically justified.

2.1.9 Evaluation

The purpose of the stability study is to establish, based on testing
a minimum of <two> batches of the drug substance and evaluating
the stability information (including, as appropriate, results of the physical,
chemical, biological, and microbiological tests), a retest period applicable
to all future batches of the drug substance manufactured under similar
circumstances. The degree of variability of individual batches affects
the confidence that a future production batch will remain within specification
throughout the assigned retest period.

The data may show so little degradation and so little variability that
it is apparent from looking at the data that the requested retest period
will be granted. Under these circumstances, it is normally unnecessary
to go through the formal statistical analysis; providing a justification
for the omission should be sufficient.

An approach for analyzing the data on a quantitative attribute that
is expected to change with time is to determine the time at which the
95% one-sided confidence limit for the mean curve intersects the acceptance
criterion. If analysis shows that the batch-to-batch variability is small,
it is advantageous to combine the data into one overall estimate. This
can be done by first applying appropriate statistical tests (e.g., p values
for level of significance of rejection of more than 0.25) to the slopes
of the regression lines and zero time intercepts for the individual batches.
If it is inappropriate to combine data from several batches, the overall
retest period should be based on the minimum time a batch can be expected
to remain within acceptance criteria.

The nature of any degradation relationship will determine whether the
data should be transformed for linear regression analysis. Usually the
relationship can be represented by a linear, quadratic, or cubic function
on an arithmetic or logarithmic scale. Statistical methods should be employed
to test the goodness of fit of the data on all batches and combined batches
(where appropriate) to the assumed degradation line or curve.

Limited extrapolation of the real time data from the long term storage
condition beyond the observed range to extend the retest period can be
undertaken at approval time, if justified. This justification should be
based on what is known about the mechanism of degradation, the results
of testing under accelerated conditions, the goodness of fit of any mathematical
model, batch size, existence of supporting stability data, etc. However,
this extrapolation assumes that the same degradation relationship will
continue to apply beyond the observed data.

Any evaluation should cover not only the assay, but also the levels
of degradation products and other appropriate attributes.

<Sponsors should consult ICHQ1E for details on the evaluation of
stability data. In addition to providing complete stability information
in submission volumes, sponsors should produce an accurate summary of
the stability data as part of the Quality Overall Summary (QOS).>

2.1.10 Statements/Labelling

A storage statement should be established for labelling. The statement
should be based on the stability evaluation of the drug substance. Where
applicable, specific instructions should be provided, particularly for
drug substances that cannot tolerate freezing. Terms such as "ambient
conditions" or "room temperature" should be avoided.

<This would normally include a storage temperature range specified
in degrees Celsius. Where applicable, specific precautions should be stated,
e.g., "Protect from light", "Protect from freezing".
Note: The use of precautionary statements should not be a substitute for
selecting the appropriate container closure system for the bulk drug substance.>

A retest period should be derived from the stability information, and
a retest date should be displayed on the container label, if appropriate.

2.2 Drug Products

2.2.1 General

The design of the formal stability studies for the drug product should
be based on knowledge of the behaviour and properties of the drug substance
and from stability studies on the drug substance and on experience gained
from clinical formulation studies. The likely changes on storage and the
rationale for the selection of attributes to be tested in the formal stability
studies should be stated.

2.2.2 Photostability Testing

Photostability testing should be conducted on at least one primary batch
of the drug product if appropriate. The standard conditions for photostability
testing are described in ICHQ1B.

2.2.3 Selection of Batches

Data from stability studies should be provided on at least <two>
primary batches of the drug product. The primary batches should be of
the same formulation and packaged in the same container closure system
as proposed for marketing. The manufacturing process used for primary
batches should simulate that to be applied to production batches and should
provide product of the same quality and meeting the same specification
as that intended for marketing. <One> of the <two> batches
should be at least pilot scale batches and the <second> one can
be smaller, if justified <(e.g., for solid oral dosage forms, a smaller
batch is generally 25 000 or 50 000 dosage units). The larger of the two
batches would be the batch used for comparative bioavailability studies,
if applicable.>. Where possible, batches of the drug product should
be manufactured by using different batches of the drug substance.

<Note: In order to qualify under the Health Canada policy on Extension
of Expiration Dates, sponsors need to have complete long term data on three production scale batches.>

Stability studies should be performed on each individual strength and
container size of the drug product unless bracketing or matrixing is applied.

Other supporting data can be provided.

<ICHQ1D should be consulted for details on bracketing and matrixing
designs. The use of any reduced design should be justified.

Justification should include a discussion of factors which could affect
the stability profile of the drug product (e.g., qualitative and/or quantitative
differences in formulation, differences in batch size, and impact of manufacturing
process parameters (such as equipment capacity and load, residence time
in a humid phase)). Supporting documentation, such as results of drug/excipient
compatibility studies or stability studies conducted on laboratory scale
batches, should be provided.

Examples of stability designs include:

Scenario 1 - a single strength:

A minimum of two batches should be placed on stability.

Scenario 2 - multiple strengths of identical formulations:

Identical formulations are those where a common blend containing identical
components in identical proportions is manufactured by the same process
and is compressed to multiple strengths. If a coating is present, the
composition of the coating is identical for all strengths. Bracketing
or matrixing designs may be acceptable if scientifically justified. A
minimum of two common blends should be manufactured. These can be compressed
to each of the proposed strengths. If bracketing is proposed, batches
of the highest and lowest strengths, resulting from the two common blends,
should be placed on stability.

Scenario 3 - multiple strengths of closely related formulations:

Closely related formulations are considered different strengths with
formulations that differ only in minor excipients (e.g., colourants or
flavourings); or that differ by minor amounts of the same excipients.

If closely related formulations differ in the relative amount of excipients,
bracketing may be acceptable if justified. A minimum of two batches of
the highest strength and two batches of the lowest strength should be
placed on stability. One batch of each of the intermediate (bracketed)
strengths should be manufactured and certificates of analyses should be
provided.

For formulations which differ in the composition of minor excipients
(e.g., colourants, flavourings), supporting stability data should be provided
to demonstrate excipient compatibility and justify bracketing. Stability
data on the intermediate (bracketed) strengths may not be necessary if
formulations are closely related.

A minimum of two batches of each strength should be placed on stability,
bracketing is not permissible.

The Health Canada policy Bioequivalence of Proportional Formulations should be used in the assessment to establish if the formulations are
considered proportional (e.g., closely related). This policy outlines
acceptable variations depending on the function of the excipient (e.g.,
fillers, disintegrants, lubricants).>

2.2.4 Container Closure System

Stability testing should be conducted on the dosage form packaged in
the container closure system proposed for marketing (including, as appropriate,
any secondary packaging and container label). Any available studies carried
out on the drug product outside its immediate container or in other packaging
materials can form a useful part of the stress testing of the dosage form
or can be considered as supporting information, respectively.

2.2.5 Specifications

Specification, which is a list of tests, reference to analytical procedures,
and proposed acceptance criteria, including the concept of different acceptance
criteria for release and shelf life specifications, is addressed in ICHQ6A. In addition, specification for degradation products in a drug product
is addressed in Q3B <and Health Canada's Impurities in Existing
Drug Substances and Products.>

Stability studies should include testing of those attributes of the
drug product that are susceptible to change during storage and are likely
to influence quality, safety, and/or efficacy. The testing should cover,
as appropriate, the physical, chemical, biological, and microbiological
attributes, preservative content (e.g., antioxidant, antimicrobial preservative),
and functionality tests (e.g., for a dose delivery system). Analytical
procedures should be fully validated and stability indicating. Whether
and to what extent replication should be performed will depend on the
results of validation studies.

Shelf life acceptance criteria should be derived from consideration
of all available stability information. It may be appropriate to have
justifiable differences between the shelf life and release acceptance
criteria based on the stability evaluation and the changes observed on
storage. Any differences between the release and shelf life acceptance
criteria for antimicrobial preservative content should be supported by
a validated correlation of chemical content and preservative effectiveness
demonstrated during drug development on the product in its final formulation
(except for preservative concentration) intended for marketing. A single
primary stability batch of the drug product should be tested for antimicrobial
preservative effectiveness (in addition to preservative content) at the
proposed shelf life for verification purposes, regardless of whether there
is a difference between the release and shelf life acceptance criteria
for preservative content.

<The concept of "release and shelf life specifications"
versus "regulatory acceptance criteria" is described in ICHQ6A. Health Canada would consider either approach acceptable. More stringent
release acceptance criteria may be necessary in certain cases in order
to ensure that shelf life acceptance criteria are met throughout the labelled
shelf life of the drug product.>

2.2.6 Testing Frequency

For long term studies, frequency of testing should be sufficient to
establish the stability profile of the drug product. For products with
a proposed shelf life of at least 12 months, the frequency of testing
at the long term storage condition should normally be every 3 months over
the first year, every 6 months over the second year, and annually thereafter
through the proposed shelf life.

At the accelerated storage condition, a minimum of three time points,
including the initial and final time points (e.g., 0, 3, and 6 months),
from a 6-month study is recommended. Where an expectation (based on development
experience) exists that results from accelerated testing are likely to
approach significant change criteria, increased testing should be conducted
either by adding samples at the final time point or by including a fourth
time point in the study design.

When testing at the intermediate storage condition is called for as
a result of significant change at the accelerated storage condition, a
minimum of four time points, including the initial and final time points
(e.g., 0, 6, 9, 12 months), from a 12-month study is recommended.

Reduced designs, i.e., matrixing or bracketing, where the testing frequency
is reduced or certain factor combinations are not tested at all, can be
applied, if justified.

2.2.7 Storage Conditions

In general, a drug product should be evaluated under storage conditions
(with appropriate tolerances) that test its thermal stability and, if
applicable, its sensitivity to moisture or potential for solvent loss.
The storage conditions and the lengths of studies chosen should be sufficient
to cover storage, shipment, and subsequent use.

Stability testing of the drug product after constitution or dilution,
if applicable, should be conducted to provide information for the labelling
on the preparation, storage condition, and in-use period of the constituted
or diluted product. This testing should be performed on the constituted
or diluted product through the proposed in-use period on primary batches
as part of the formal stability studies at initial and final time points
and, if full shelf life long term data will not be available before submission,
at <6> months or the last time point for which data will be available.
In general, this testing need not be repeated on commitment batches.

The long term testing should cover a minimum of <6> months' duration
on at least <two> primary batches at the time of submission and
should be continued for a period of time sufficient to cover the proposed
shelf life. Additional data accumulated during the assessment period of
the registration application should be submitted to the authorities if
requested. Data from the accelerated storage condition and, if appropriate,
from the intermediate storage condition can be used to evaluate the effect
of short term excursions outside the label storage conditions (such as
might occur during shipping).

Long term, accelerated, and, where appropriate, intermediate storage
conditions for drug products are detailed in the sections below. The general
case applies if the drug product is not specifically covered by a subsequent
section. Alternative storage conditions can be used, if justified.

2.2.7.1 General Case

Study

Storage conditions

Minimum time period
covered by data at submission

It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/60% RH ± 5% RH or 30°C ± 2°C/65% RH ± 5% RH.

If 30°C ± 2°C/65% RH ± 5% RH is the long-term condition, there is no intermediate condition.

Long-term

25°C ± 2°C / 60% RH ± 5%
or 30°C ± 2°C/65% RH ± 5% RH

<6> months

Intermediate

30°C ± 2°C/65% RH ± 5% RH

6 months

Accelerated

40°C ± 2°C / 75% RH ± 5%

6 months

If long-term studies are conducted at 25°C ± 2°C/60% RH ±
5% RH and "significant change" occurs at any time during 6 months'
testing at the accelerated storage condition, additional testing at the
intermediate storage condition should be conducted and evaluated against
significant change criteria. The initial application should include a
minimum of 6 months' data from a 12-month study at the intermediate storage
condition.

In general, "significant change" for a drug product is defined
as:

A 5% change in assay from its initial value; or failure to meet the
acceptance criteria for potency when using biological or immunological
procedures;

Any degradation product's exceeding its acceptance criterion;

Failure to meet the acceptance criteria for appearance, physical attributes,
and functionality test (e.g., color, phase separation, resuspendibility,
caking, hardness, dose delivery per actuation); however, some changes
in physical attributes (e.g., softening of suppositories, melting of
creams) may be expected under accelerated conditions;

and, as appropriate for the dosage form:

Failure to meet the acceptance criterion for pH; or

Failure to meet the acceptance criteria for dissolution for 12 dosage
units.

2.2.7.2 Drug Products Packaged in Impermeable Containers

Sensitivity to moisture or potential for solvent loss is not a concern
for drug products packaged in impermeable containers that provide a permanent
barrier to passage of moisture or solvent. Thus, stability studies for
products stored in impermeable containers can be conducted under any controlled
or ambient humidity condition.

2.2.7.3 Drug Products Packaged in Semi-Permeable Containers

Aqueous-based products packaged in semi-permeable containers should
be evaluated for potential water loss in addition to physical, chemical,
biological, and microbiological stability. This evaluation can be carried
out under conditions of low relative humidity, as discussed below. Ultimately,
it should be demonstrated that aqueous-based drug products stored in semi-permeable
containers can withstand low relative humidity environments.

Other comparable approaches can be developed and reported for non-aqueous,
solvent-based products.

Drug Products Packaged in Semi-Permeable Containers

Study

Storage condition

Minimum time period
covered by data at submission

It is up to the applicant to decide whether long term stability studies are performed at 25 ± 2°C/40% RH ± 5% RH or 30°C ± 2°C/35% RH ± 5% RH.

If 30°C ± 2°C/35% RH ± 5% RH is the long-term condition, there is no intermediate condition.

Long term

25°C ± 2°C/40% RH ± 5% RH
or 30°C ± 2°C/35% RH ± 5% RH

<6> months

Intermediate

30°C ± 2°C/65% RH ± 5% RH

6 months

Accelerated

40°C ± 2°C/not more than (NMT) 25% RH

6 months

For long-term studies conducted at 25°C ± 2°C/40% RH ±
5% RH, additional testing at the intermediate storage condition should
be performed as described under the general case to evaluate the temperature
effect at 30°C if significant change other than water loss occurs during
the 6 months' testing at the accelerated storage condition. A significant
change in water loss alone at the accelerated storage condition does not
necessitate testing at the intermediate storage condition. However, data
should be provided to demonstrate that the drug product will not have
significant water loss throughout the proposed shelf life if stored at
25°C and the reference relative humidity of 40% RH.

A 5% loss in water from its initial value is considered a significant
change for a product packaged in a semi-permeable container after an equivalent
of 3 months' storage at 40°C/NMT 25% RH. However, for small containers
(1 mL or less) or unit-dose products, a water loss of 5% or more after
an equivalent of 3 months' storage at 40°C/NMT 25% RH may be appropriate,
if justified.

An alternative approach to studying at the reference relative humidity
as recommended in the table above (for either long term or accelerated
testing) is performing the stability studies under higher relative humidity
and deriving the water loss at the reference relative humidity through
calculation. This can be achieved by experimentally determining the permeation
coefficient for the container closure system or, as shown in the example
below, using the calculated ratio of water loss rates between the two
humidity conditions at the same temperature. The permeation coefficient
for a container closure system can be experimentally determined by using
the worst case scenario (e.g., the most diluted of a series of concentrations)
for the proposed drug product.

Example of an approach for determining water loss:

For a product in a given container closure system, container size, and
fill, an appropriate approach for deriving the water loss rate at the
reference relative humidity is to multiply the water loss rate measured
at an alternative relative humidity at the same temperature by a water
loss rate ratio shown in the table below. A linear water loss rate at
the alternative relative humidity over the storage period should be demonstrated.

For example, at a given temperature, e.g., 40°C, the calculated water
loss rate during storage at NMT 25% RH is the water loss rate measured
at 75% RH multiplied by 3.0, the corresponding water loss rate ratio.

Example of an approach for determining water loss

Alternative relative humidity

Reference relative humidity

Ratio of water loss rates at a given temperature

60% RH

25% RH

1.9

60% RH

40% RH

1.5

65% RH

35% RH

1.9

75% RH

25% RH

3

Valid water loss rate ratios at relative humidity conditions other than
those shown in the table above can also be used.

2.2.7.4 Drug Products Intended for Storage in a Refrigerator

Study

Storage condition

Minimum time period
covered by data at submission

Long term

5°C ± 3°C

<6> months

Accelerated

25°C ± 2°C/60% RH ± 5%RH

6 months

If the drug product is packaged in a semi-permeable container, appropriate
information should be provided to assess the extent of water loss.

Data from refrigerated storage should be assessed according to the evaluation
section of this guidance, except where explicitly noted below.

If significant change occurs between 3 and 6 months' testing at the
accelerated storage condition, the proposed shelf life should be based
on the real time data available from the long term storage condition.

If significant change occurs within the first 3 months' testing at the
accelerated storage condition, a discussion should be provided to address
the effect of short term excursions outside the label storage condition,
e.g., during shipment and handling. This discussion can be supported,
if appropriate, by further testing on a single batch of the drug product
for a period shorter than 3 months but with more frequent testing than
usual. It is considered unnecessary to continue to test a product through
6 months when a significant change has occurred within the first 3 months.

2.2.7.5 Drug Products Intended for Storage in a Freezer

Study

Storage condition

Minimum time period covered by data at submission

Long term

- 20°C ± 5°C

<6> months

For drug products intended for storage in a freezer, the shelf life should
be based on the real time data obtained at the long term storage condition.
In the absence of an accelerated storage condition for drug products intended
to be stored in a freezer, testing on a single batch at an elevated temperature
(e.g., 5°C ± 3°C or 25°C ± 2°C) for an appropriate time
period should be conducted to address the effect of short term excursions
outside the proposed label storage condition.

2.2.7.6 Drug Products Intended for Storage below
-20°c

Drug products intended for storage below -20°C should be treated on
a case-by-case basis.

2.2.8 Stability Commitment

When available long term stability data on primary batches do not cover
the proposed shelf life granted at the time of approval, a commitment
should be made to continue the stability studies post approval in order
to firmly establish the shelf life.

Where the submission includes long term stability data from <two>
production batches covering the proposed shelf life, a post approval commitment
is considered unnecessary. Otherwise, one of the following commitments
should be made:

If the submission includes data from stability studies on at least
<two> production batches, a commitment should be made to continue
the long term studies through the proposed shelf life and the accelerated
studies for 6 months.

If the submission includes data from stability studies on fewer than
<two> production batches, a commitment should be made to continue
the long term studies through the proposed shelf life and the accelerated
studies for 6 months, and to place additional production batches, to
a total of at least <two>, on long term stability studies through
the proposed shelf life and on accelerated studies for 6 months.

If the submission does not include stability data on production batches,
a commitment should be made to place the first <two> production
batches on long term stability studies through the proposed shelf life
and on accelerated studies for 6 months.

The stability protocol used for studies on commitment batches should
be the same as that for the primary batches, unless otherwise scientifically
justified.

Where intermediate testing is called for by a significant change at
the accelerated storage condition for the primary batches, testing on
the commitment batches can be conducted at either the intermediate or
the accelerated storage condition. However, if significant change occurs
at the accelerated storage condition on the commitment batches, testing
at the intermediate storage condition should also be conducted.

2.2.9 Evaluation

A systematic approach should be adopted in the presentation and evaluation
of the stability information, which should include, as appropriate, results
from the physical, chemical, biological, and microbiological tests, including
particular attributes of the dosage form (for example, dissolution rate
for solid oral dosage forms).

The purpose of the stability study is to establish, based on testing
a minimum of <two> batches of the drug product, a shelf life and
label storage instructions applicable to all future batches of the drug
product manufactured and packaged under similar circumstances. The degree
of variability of individual batches affects the confidence that a future
production batch will remain within specification throughout its shelf
life.

Where the data show so little degradation and so little variability
that it is apparent from looking at the data that the requested shelf
life will be granted, it is normally unnecessary to go through the formal
statistical analysis; providing a justification for the omission should
be sufficient.

An approach for analyzing data of a quantitative attribute that is expected
to change with time is to determine the time at which the 95 one-sided
confidence limit for the mean curve intersects the acceptance criterion.
If analysis shows that the batch-to-batch variability is small, it is
advantageous to combine the data into one overall estimate. This can be
done by first applying appropriate statistical tests (e.g., p values for
level of significance of rejection of more than 0.25) to the slopes of
the regression lines and zero time intercepts for the individual batches.
If it is inappropriate to combine data from several batches, the overall
shelf life should be based on the minimum time a batch can be expected
to remain within acceptance criteria.

The nature of the degradation relationship will determine whether the
data should be transformed for linear regression analysis. Usually the
relationship can be represented by a linear, quadratic, or cubic function
on an arithmetic or logarithmic scale. Statistical methods should be employed
to test the goodness of fit on all batches and combined batches (where
appropriate) to the assumed degradation line or curve.

Limited extrapolation of the real time data from the long term storage
condition beyond the observed range to extend the shelf life can be undertaken
at approval time, if justified. This justification should be based on
what is known about the mechanisms of degradation, the results of testing
under accelerated conditions, the goodness of fit of any mathematical
model, batch size, existence of supporting stability data, etc. However,
this extrapolation assumes that the same degradation relationship will
continue to apply beyond the observed data.

Any evaluation should consider not only the assay but also the degradation
products and other appropriate attributes. Where appropriate, attention
should be paid to reviewing the adequacy of the mass balance and different
stability and degradation performance.

<Sponsors should consult ICHQ1E for details on the evaluation of
stability data. In addition to providing complete study information in
submission volumes, sponsors should to produce an accurate summary of
stability data as part of the Quality Overall Summary (QOS).>

2.2.10 Statements/Labelling

A storage statement should be established for the labelling. The statement
should be based on the stability evaluation of the drug product. Where
applicable, specific instructions should be provided, particularly for
drug product that cannot tolerate freezing. Terms such as "ambient
conditions" or "room temperature" should be avoided.

There should be a direct link between the label storage statement and
the demonstrated stability of the drug product. An expiration date should
be displayed on the container label.

<Labelling would normally include a storage temperature range specified
in degrees Celsius. Where applicable, specific precautions should be stated,
e.g., "Protect from light", "Protect from freezing".
Note: The use of precautionary statements should not be a substitute for
selecting the appropriate container closure system for the drug product.

If the results from the stability studies demonstrate that the drug
product is acceptable under the General Case (section 2.2.7), the following
are examples of acceptable storage statements:

When only a maximum storage temperature is proposed (e.g., "Store
up to
25°C"), sponsors should provide stability data to demonstrate
that the product is not adversely affected by low temperature storage
conditions
(e.g., 5°C ± 3°C).

2.2.11 Continuing Stability Studies

<A Continuing Stability Programme (i.e. ongoing stability
studies) should be implemented to ensure compliance with the approved
shelf life specifications. A minimum of one batch of every strength of
the drug product should be enrolled into the continuing stability programme
each year. Bracketing and matrixing can be applied, if scientifically
justified.>

3 Glossary

The following definitions are provided to facilitate interpretation of
the guidance.

Accelerated Testing

Studies designed to increase the rate of
chemical degradation or physical change of a drug substance or drug product
by using exaggerated storage conditions as part of the formal stability
studies. Data from these studies, in addition to long term stability studies,
can be used to assess longer term chemical effects at non-accelerated
conditions and to evaluate the effect of short term excursions outside
the label storage conditions such as might occur during shipping. Results
from accelerated testing studies are not always predictive of physical
changes.

Bracketing

The design of a stability schedule such that only
samples on the extremes of certain design factors, e.g., strength, package
size, are tested at all time points as in a full design. The design assumes
that the stability of any intermediate levels is represented by the stability
of the extremes tested. Where a range of strengths is to be tested, bracketing
is applicable if the strengths are identical or very closely related in
composition (e.g., for a tablet range made with different compression
weights of a similar basic granulation, or a capsule range made by filling
different plug fill weights of the same basic composition into different
size capsule shells). Bracketing can be applied to different container
sizes or different fills in the same container closure system.

Climatic Zones

The four zones in the world that are distinguished
by their characteristic prevalent annual climatic conditions. This is
based on the concept described by W. Grimm (Drugs Made in Germany, 28:196-202,
1985 and 29:39-47, 1986).

Commitment Batches

Production batches of a drug substance or
drug product for which the stability studies are initiated or completed
post approval through a commitment made in the registration application.

Container Closure System

The sum of packaging components that
together contain and protect the dosage form. This includes primary packaging
components and secondary packaging components, if the latter are intended
to provide additional protection to the drug product. A packaging system
is equivalent to a container closure system.

Dosage Form

A pharmaceutical product type (e.g., tablet, capsule,
solution, cream) that contains a drug substance generally, but not necessarily,
in association with excipients.The dosage form in the final immediate packaging intended for marketing.

Drug Substance

The unformulated drug substance that may subsequently
be formulated with excipients to produce the dosage form.

Excipient

Anything other than the drug substance in the dosage form.

Expiration Date

The date placed on the container label of a
drug product designating the time prior to which a batch of the product
is expected to remain within the approved shelf life specification if
stored under defined conditions, and after which it must not be used.

Formal Stability Studies

Long term and accelerated (and intermediate)
studies undertaken on primary and/or commitment batches according to a
prescribed stability protocol to establish or confirm the re-test period
of a drug substance or the shelf life of a drug product.

Impermeable Containers

Containers that provide a permanent barrier
to the passage of gases or solvents, e.g., sealed aluminum tubes for semi-solids,
sealed glass ampoules for solutions.

Intermediate Testing

Studies conducted at 30°C/65% RH and designed
to moderately increase the rate of chemical degradation or physical changes
for a drug substance or drug product intended to be stored long term at
25°C.

Long Term Testing

Stability studies under the recommended storage
condition for the retest period or shelf life proposed (or approved) for
labelling.

Mass Balance

The process of adding together the assay value
and levels of degradation products to see how closely these add up to
100% of the initial value, with due consideration of the margin of analytical
error.

Matrixing

The design of a stability schedule such that a selected
subset of the total number of possible samples for all factor combinations
is tested at a specified time point. At a subsequent time point, another
subset of samples for all factor combinations is tested. The design assumes
that the stability of each subset of samples tested represents the stability
of all samples at a given time point. The differences in the samples for
the same drug product should be identified as, for example, covering different
batches, different strengths, different sizes of the same container closure
system, and, possibly in some cases, different container closure systems.

Mean Kinetic Temperature

A single derived temperature that,
if maintained over a defined period of time, affords the same thermal
challenge to a drug substance or drug product as would be experienced
over a range of both higher and lower temperatures for an equivalent defined
period. The mean kinetic temperature is higher than the arithmetic mean
temperature and takes into account the Arrhenius equation.
When establishing the mean kinetic temperature for a defined period, the
formula of J. D. Haynes (J. Pharm. Sci., 60:927-929, 1971) can be used.

New Molecular Entity

An active pharmaceutical substance not
previously contained in any drug product registered with the national
or regional authority concerned. A new salt, ester, or non-covalent-bond
derivative of an approved drug substance is considered a new molecular
entity for the purpose of stability testing under this guidance.

Pilot Scale Batch

A batch of a drug substance or drug product
manufactured by a procedure fully representative of and simulating that
to be applied to a full production scale batch. For solid oral dosage
forms, a pilot scale is generally, at a minimum, one-tenth that of a full
production scale or 100,000 tablets or capsules, whichever is the larger.

Primary Batch

A batch of a drug substance or drug product used
in a formal stability study, from which stability data are submitted in
a registration application for the purpose of establishing a retest period
or shelf life, respectively. A primary batch of a drug substance should
be at least a pilot scale batch. For a drug product, <one> of the
<two> batches should be at least pilot scale batch, and the <second>
batch can be smaller if it is representative with regard to the critical
manufacturing steps. However, a primary batch may be a production batch.

Production Batch

A batch of a drug substance or drug product
manufactured at production scale by using production equipment in a production
facility as specified in the application.

Retest Date

The date after which samples of the drug substance
should be examined to ensure that the material is still in compliance
with the specification and thus suitable for use in the manufacture of
a given drug product.

Retest Period

The period of time during which the drug substance
is expected to remain within its specification and, therefore, can be
used in the manufacture of a given drug product, provided that the drug
substance has been stored under the defined conditions. After this period,
a batch of drug substance destined for use in the manufacture of a drug
product should be retested for compliance with the specification and then
used immediately. A batch of drug substance can be retested multiple times
and a different portion of the batch used after each retest, as long as
it continues to comply with the specification. For most biotechnological/biological
substances known to be labile, it is more appropriate to establish a shelf
life than a retest period. The same may be true for certain antibiotics.

Semi-permeable Containers

Containers that allow the passage
of solvent, usually water, while preventing solute loss. The mechanism
for solvent transport occurs by absorption into one container surface,
diffusion through the bulk of the container material, and desorption from
the other surface. Transport is driven by a partial-pressure gradient.
Examples of semi-permeable containers include plastic bags and semi-rigid,
low-density polyethylene (LDPE) pouches for large volume parenterals (LVPs),
and LDPE ampoules, bottles, and vials.

Shelf Life (also referred to as expiration dating period)

The
time period during which a drug product is expected to remain within the
approved shelf life specification, provided that it is stored under the
conditions defined on the container label.

Specification

See Q6A.

Specification - Release

The combination of physical, chemical,
biological, and microbiological tests and acceptance criteria that determine
the suitability of a drug product at the time of its release.

Specification - Shelf life

The combination of physical, chemical,
biological, and microbiological tests and acceptance criteria that determine
the suitability of a drug substance throughout its retest period, or that
a drug product should meet throughout its shelf life.

Storage Condition Tolerances

The acceptable variations in temperature
and relative humidity of storage facilities for formal stability studies.
The equipment should be capable of controlling the storage condition within
the ranges defined in this guidance. The actual temperature and humidity
(when controlled) should be monitored during stability storage. Short
term spikes due to opening of doors of the storage facility are accepted
as unavoidable. The effect of excursions due to equipment failure should
be addressed, and reported if judged to affect stability results. Excursions
that exceed the defined tolerances for more than 24 hours should be described
in the study report and their effect assessed.

Stress Testing (drug substance)

Studies undertaken to elucidate
the intrinsic stability of the drug substance. Such testing is part of
the development strategy and is normally carried out under more severe
conditions than those used for accelerated testing.

Data, other than those from formal stability
studies, that support the analytical procedures, the proposed retest period
or shelf life, and the label storage statements. Such data include (1)
stability data on early synthetic route batches of drug substance, small
scale batches of materials, investigational formulations not proposed
for marketing, related formulations, and product presented in containers
and closures other than those proposed for marketing; (2) information
regarding test results on containers; and (3) other scientific rationales.